Nerve growth factor (NGF) is a small secreted protein that is involved in the regulation of growth and differentiation of sympathetic and sensory neurons (Levi-Montalcini, Science, 294: 1945-1948 (2001), and Freeman et al., Prog. Brain Res., 146: 111-126 (2004)). NGF is involved in a variety of processes involving signaling, such as cell differentiation and survival, growth cessation, and apoptosis of neurons. These events are mediated by NGF as a result of binding to its two cell-surface receptors, TrkA and p75. TrkA is a receptor with tyrosine kinase activity that forms a high-affinity binding site for NGF.
The role of NGF in neural development has been characterized extensively (see, e.g., Patel et al., Neuron, 25(2): 345-357 (2000)), but recent findings suggest that NGF plays a role in a variety of biological pathways, and that developmental effects are only one aspect of the biology of NGF. For example, endogenous NGF signaling is involved in neuroprotective and repair functions (see, e.g., Sofroniew et al., Annu. Rev. Neurosci., 24: 1217-1281 (2001)). NGF signaling also has been implicated in Alzheimer's disease (see, e.g., Calissano et al., Dev. Neurobiol., 70(5): 372-383 (2010)), inflammation (see, e.g., Freund et al., Prog. Brain Res., 146: 335-346 (2004), and Levi-Montalcini, Trends in Neurosciences, 19(11): 514-520 (1996)), and pain transduction mechanisms (see, e.g., Watson et al., Bio Drugs, 22(6): 349-359 (2008), and Cattaneo, Curr. Opin. Mol. Ther., 12(1): 94-106 (2010)).
The expression of NGF is high in injured and inflamed tissues, and activation of TrkA on nociceptive neurons triggers and potentiates pain signaling by multiple mechanisms (see, e.g., Hefti et al., Trends in Pharmacological Sciences, 27: 85-91 (2006)). Both local and systemic administration of NGF have been shown to elicit hyperalgesia and allodynia (Lewin et al., Eur. J. Neurosci., 6: 1903-1912 (1994)). Intravenous infusion of NGF in humans produces a whole body myalgia while local administration evokes injection site hyperalgesia and allodynia in addition to the systemic effects (Apfel et al., Neurology, 51: 695-702 (1998)). Endogenous NGF also has been implicated in conditions in which pain is a prominent feature. For example, NGF is upregulated in dorsal root ganglion (DRG) Schwann cells for at least two months following peripheral nerve injury, and increased levels of NGF have been reported in the joints of animal models of arthritis (see, e.g., Aloe et al., Growth Factors, 9: 149-15 (1993)). In humans, NGF levels are elevated in synovial fluid from patients with rheumatoid or other types of arthritis (see, e.g., Aloe et al., Arthritis and Rheumatism, 35: 351-355 (1992)).
Inhibition of NGF function has been shown to prevent hyperalgesia and allodynia in models of neuropathic and chronic inflammatory pain. For example, in animal models of neuropathic pain, systemic injection of neutralizing antibodies to NGF inhibits both allodynia and hyperalgesia (see, e.g., Ramer et al., Eur. J. Neurosci., 11: 837-846 (1999), and Ro et al., Pain, 79: 265-274 (1999)). Other antibodies specific for NGF have been described (see, e.g., U.S. Pat. Nos. 5,844,092, 5,877,016, 6,153,189, and 7,601,818; U.S. Patent Application Publication No. 2009/0123464 A1, International Patent Application Publication Nos. WO 2001/78698, WO 2001/64247, WO 2002/096458, WO 2004/032870, WO 2005/044293, WO 2005/061540, and WO 2006/131951; Hongo et al., Hybridoma, 19: 215-227 (2000), and Hongo et al., Cell. Mol. Biol., 13: 559-568 (1993)). However, the therapeutic utility of currently available NGF antibodies is limited by their sub-optimum pharmacokinetics, stability, and efficacy in vivo.
Therefore, there is a need for an NGF-binding agent (e.g., an antibody) which binds NGF with a high affinity, exhibits increased stability and improved pharmacokinetics, and effectively neutralizes NGF activity in vivo. The invention provides such NGF binding agents.